1. Field of the Invention
The present invention relates to amido substituted naphthalenes of general formula I: ##STR1## or their intermediates of general formula II: ##STR2## as described further below, and to a method for synthesizing the naphthalene derivatives. The amido substituted naphthalenes are pharmacologically active in alleviating inflammation, asthma, hypersensitivity, myocardial ischemia, dermatological conditions such as psoriasis, and dermatitis and gastrointestinal inflammatory conditions such as inflammatory bowel syndromes.
2. Description of the Prior Art
Nonosteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, naproxen, ibuprofen, tolectin, fenoprofen and the like have generally been shown to attenuate the biosynthesis of prostaglandins by inhibiting the activity of the enzyme cyclooxygenase. The prostaglandin end-products of the cyclooxygenase pathway are responsible for many of the early signs of inflammation including peralgesia, increases in vascular permeability leading to edema, and pyrexia. The activity and potency of the NSAIDs in reducing these signs and symptoms is, for the most part, correlated with their ability to inhibit prostaglandin biosynthesis.
The other major pathway of arachidonic acid metabolism is the lipoxygenase pathway. Lipoxygenase products of arachidonate metabolism, the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and hydroperoxyeicosatetraenoic acids, have been shown or implicated to be involved in disease states including acute and chronic inflammation, arthritis, allergic and other hypersensitivity disorders, dermatological diseases such as psoriasis, acne, atopic dermatitis, contact sensitivity, eczema and others, cardiovascular disorders secondary to myocardial ischemia such as infarction, thromboembolism or vasculities, or platelet aggregation, and hyperalgesic disorders, gynecological disorders such as dysmenorrhea, ocular inflammation, and gastrointestinal disorders such as inflammatory bowel diseases.
Leukotriene B.sub.4, another product of the lipoxygenase pathway, as well as the hydroxyeicosatetraenoic acids and hydroperoxyeicosatetraenoic acids, can mediate induction of other phlogistic substances such as thromboxanes and prostacyclin, is chemotactic to inflammatory cells, and is hyperalgesic. Many of these mediators have been identified in skin, lungs, coronary circulation, eyes and other organs and in the synovial fluid of rheumatoid arthritic patients. In chronic inflammatory conditions such as rheumatoid arthritis, it is believed to be the chronic influx of leukocytes, probably mediated by leukotriene B.sub.4, that is the eventual cause of joint erosion.
It is believed that inhibitors of the lipoxygenase pathway could lead to a relatively permanent effect on inflammatory disorders such as rheumatoid arthritis since they could modulate the actual mechanism of tissue and joint breakdown. Similarly, drugs that could inhibit prostaglandin synthesis via the cyclooxygenase pathway could modulate and reduce early manifestations of inflammation. Pharmacologically active compounds that can inhibit both enzyme pathways at similar concentrations (dual inhibitors) provide a more complete relief for patients suffering from arthritis, hypersensitivity, dermatological, cardiovascular, ocular, and gynecological disorders than present drugs that inhibit one pathway but not the other, as is the case for usually used NSAIDs that are predominantly inhibitors of the cyclooxygenase (prostaglandin synthesis) pathway.
Several naphthalene derivatives have been previously described. For example, naproxen, 6-methoxy-.alpha.-methyl-2-naphthalene acetic acid has been described as a potent anti-inflammatory agent which acts by a cyclooxygenase mechanism. J. Med. Chem. 13, 203 (1970) and Biochem. Biophys. Res. Comm. 46, 552 (1972). Naproxen is described in U.S. Pat. No. 4,637,767.
Nabumetone (BRL-14777), 4-(6-methoxy-2-naphthalenyl)-2-butanone with its analogs have been reported as anti-inflammatory agents with greatly reduced gastrointestinal complications. J. Med. Chem. 21, 1260 (1978) and Drugs of the Future VI, p. 35 (1981). Nabumetone is described in British Pat. No. 1,474,377.
In addition, several oxoalkanoic acid or ester substituted naphthalenes have been previously described. For example, 4-(6-methoxy-2-naphthyl)-4-oxobutyric acid and its esters have been described as intermediates for the synthesis of other compounds in Beilstein 10, 3rd Suppl., pp. 4414-5; Chimia 18, 141 (1964); Czech. Coll. Chem. Communs. 26, 1475 (1961) and J. Org. Chem. 25, 1856 (1960).
6-(6-methoxy-2-naphthyl)-6-oxohexanoic acid was prepared in Bull. Chem. Socl. Fr., 1959, pp. 1943-6, by the action of acid chlorides on tetrahydropyranyl esters of HO.sub.2 CCH.sub.2 CH.sub.2 (CH.sub.2).sub.2 CO.sub.2 H. This reaction had not been previously reported, and circumvented the use of acid chlorides of dibasic acids in a Friedel-Crafts type acylation. 5-(6-methoxy-2-naphthyl)-5-oxopentanoic acid was prepared in a similar manner as reported in Croat. Chem. Acta 41, 251 (1969).
None of the prior art directed to the oxoalkanoic acid or ester substituted naphthalenes describes any biological activity for the compounds. None of this prior art describes amido substituted naphthalene compounds.